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Publication numberUS3857873 A
Publication typeGrant
Publication dateDec 31, 1974
Filing dateFeb 11, 1974
Priority dateFeb 11, 1974
Publication numberUS 3857873 A, US 3857873A, US-A-3857873, US3857873 A, US3857873A
InventorsC Schwender, J Shavel
Original AssigneeWarner Lambert Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
3-hydroxy-5-(3-(substituted-amino)-2-hydroxypropoxy)-benzyl alcohols
US 3857873 A
Abstract
The present invention relates to novel compounds of the formula:
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Description  (OCR text may contain errors)

United States Patent [191 Schwender et al.

[111 3,857,873 [451 Dec. 31, 1974 [75] Inventors: Charles F. Schwender, Lebanon;

John Shave], Jr., Mendham, both-0f NJ.

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

[22] Filed: Feb. 11, 1974 [21] Appl. No.: 441,597

[52] U.S. Cl. 260/471 R, 260/247.2 B, 260/247.7 C, 260/293.8l, 260/293.84, 260/519, 260/570.7, 424/248, 424/267,

424/309,424/319,424/330 [5 l Hit. Cl. .If. I. .T LLTIIIT: [58] Field of Search 260/471 R, 519, 570.7

[56] References Cited UNITED STATES PATENTS 3,793,365 2/1974 Winter et a] 260/519 Primary Examiner-Lorraine A. Weinberger Assistant ExaminerL. A. Thaxton Attorney, Agent, or FirmAlbert H. Graddis; Frank s. Chow; George M. Yahwak [5 7 ABSTRACT The present invention relates to novel compounds of the formula:

R R I wherein R may be a COOH, COOCH or CH Ol-i radical, R may be a hydroxy or benzyl radical, and wherein R may be a tert. butyl or a 3,4- dimethoxyphenyl ethyl radical. These agents are useful in the treatment of cardiovascular disorders such as angina pectoris, arrhythmias and hypertension wherein B-adrenergic blockage is the desired effect. Also disclosed is the preparation of the above series of B-adrenergic blocking agents. The B-adrenergic blockage characteristic of these compounds is furthermore achieved at dosage levels which are less toxic than most other B-adrenergic blocking agents.

11 Claims, No Drawings l 3-HYDROXY-5-(IS-(SUBSTITUTED-AMINOl-Z- HYDROXYPROPOXYl-BENZYL ALCOHOLS Compounds of the present invention are those of the family of compounds encompassed by the formula:

wherein R may be a COOH. COOCH CH OH radical; R may be a hydroxy or benzyloxy radical; and wherein X and Y may be, together or separately, hy-

. drogen, a lower alkyl of up to six carbons, tert.-butyl or H CHOH CH, N

l B R2 RL OLH wherein R is selected from the group consisting of:

-COOH COOCH and -CH OH;

wherein R is selected from the group consisting of:

OH, and

-ou, and

COUCH,

HO OH OCH CHOHClhNlhR V HSCA CH2 iHdPd-cJDZ or dil.

COOCHJ wherein R is selected from the group consisting of:

- c ot and V and the pharmaceutically acceptable salts of the above at dosage levels which are much less toxic than most other B-adrenergic blocking agents.

Suitable esters ofthe above compounds with the usual pharmaceutically acceptable alcohols and acids also have utility. Among these are acetate. succinate. propionate, benzoate, and the like. as well as modifications of the oxypropanolamino side chain to the corresponding oxazolidinyl derivatives.

Pharmaceutically acceptable salts, such as hydrogen chloride and fumarate, of the above compounds have also been shown to have utility as B-adrenergic agents.

The preferred species of this invention include those analogs of formula A shown in formula B. Generally speaking, the preferred species of compounds were synthesized starting from the known precursor. methyl-3,S-dihydroxybenzoate (formula l) as follows:

COOCH moOCll HO OCOCJI,

ll III l OCH;Cll-CH1 ocmcuciuct 1 Q 01. Q coocii coocu ocn,aroaca,na,a.

ocu cuoacit NR a 2 1 3 u Ho V cmcna AatJl-l ]x no coon As shown in the preceding flow diagram. reaction of formula 1 with one equivalent of benzoyl halide gives the corresponding methyl 3-benzoy1oxy-5- hydroxybenzoate (11) which is then benzylated using benzyl bromide to give methyl 3'-benzyloxy-5-benzoyloxybenzoate (111). A transesterification of 111 using MeOH and an acid catalyst such as ethanesulfonic acid gives methyl 3-benzy1oxy-5-hydroxy-benzoate (IV). Reaction of IV with epichlorohydrin in methanolcontaining a base such as NaOH give the intermediate methyl 3-benzyloxy-5-[-2,3-epoxypropoxy and/or 3-chloro-2-hydroxypr0poxy] benzoate (V) which is- EXAMPLE 1 METHYL 3-BENZOYLOXY-5- HYDROXYBENZOATE To a solution of 168 g (1.0 mole) of methyl 3.5-dihydroxy-benzoate in 2.0 1. of water was added 30 ml of NaOH until a pH of 8.0. Benzo'yl chloride (154 g, 1.1 moles) and 400 ml of 10% NaOH were added simultaneously to the warmed reaction mixture (40) over a 30 minute period. The reaction was stirred at 3'0'35 for 1 hour and extracted with CHCL (2 750 ml). The combined CHCL extracts were washed with water (1X350 ml) and dried over MgSO Evaporation of the CHCl gave 252 g (92.8%) of the crude product. Recrystallization of the material from benzene gave 159 g (58.5%) of crystalline product; mp 1101 12.

EXAMPLE n METHYL 3-BENZOYLOXY-5-BENZYLOX- YBENZOATE A mixture of methyl 3-benzoyloxy-5- hydroxybenzoate [418 g (1.54 moles)]. benzyl bromide (387 g. 2.26 moles), K CO (310 g, 2.26 moles) and 4.1 1. of acetone was heated at reflux for 3 hours.

The mixture was poured onto 3.3 1. ice and extracted with CHCl (2X2 1.). The CHCl extracts were combined and washed with 10% NaOH (3.3 1.) and water (2X1.6 1.). The CHCl phase was dried with MgSO. and evaporated to give an oily residue which was stirred with hexane (1.8 1.) at 10 for 1 hour. Crystalline product was collected by filtration and reslurried with hexane (1.3 1.) for 1 hour at 10. The crystalline material was collected and dried to give 409 g (73.5%)

of product; mp 69-70".

mcuoacnmna. 1 o \CHZOH EXAMPLE lll METHYL 3-BENZYLOXY-5- HYDROXYBENZOATE A reaction mixture containing 409 g 1.13 moles) of methyl 3-benzoyloxy-5-be'nzyloxybenzoate, 102 g (0.55 mole) p-toluenesulfonic acid and 2.7 1. of MeOH was heated at reflux for 17 hours.,The reaction mixture was evaporated to dryness and the crude residue obtained was dissolved in CHCl (2.5 1.) and washed with aqueous NaHCO; water and dried with MgSO. before the CHCL phase was evaporated in vacuo to the crude product as an oil. Trituration of the residue with hexane yielded crystalline product; yield 220 g (75.5%); mp 97'98.

Anal. Calcd for C H O C, 69.75; H, 5.46. Found: C, 69.85; H, 5.42.

EXAMPLE 1V METHYL 3BENZYLOXY-5-(2.3-

EPOXYPROPOXY)-BENZOATE AND/OR METHYL 3-BENZYLOXY-5(3-CHLORO-2- HYDROXYPROPOXY)-BENZOATE A methanolic solution (250 ml) containing 4.26 g

(106 mmol) of NaOH, 250 ml of epichlorohydrin and 25 g (96.8 mmol) of methyl 3-benzyloxy-5- hydroxybenzoate was stirred at room temperature for 18 hours. The reaction mixture was evaporated to a residual oil which was dissolved in 500 ml CHCL;, and extracted with 10% NaOH (1Xl00 ml) and water 1 100 ml) before drying with anhydrous MgSO The CHCL was evaporated and the crude mixture of the expected products was obtained as a gum in 98% yield.

EXAMPLE V METHYL 3-BENZYLOXY-5-[3-(3.4-

DIMETHOXYPHENYLETHYLAM1N0)-2- HYDROXY-PROPOXYl-BENZOATE A reaction mixture containing 10.0 g (31.9 mmol) of methyl 3-benzyloxy-5-[2.3-epoxypropoxy or 3-chloro- 2-hydroxypropoxy]-benzoate. 25 g (138 mmol) of 3,4-dimethoxyphenylethylamine and 100 ml of methanol was heated at reflux for 1 hour. Evaporation of the reaction mixture gave a residual oil which was dissolved in CHCL (500 ml), extracted with 1N HCl (2X250 ml), 1N NaOH (500 ml). and dried with anhydrous MgSO... Evaporation of the CHCL gave a residual solid which upon trituration with a Et O-hexane mixture gave 14.6 g (92.4% )of crystalline product; mp 85. The analytical material was obtained by recrystallization from toluene; mp 9495.

Anal. Calcd for C H NO C, 67.86; H. 6.71; N.

2.83. Found: C. 67.66; H, 6.75; N. 2.65.

EXAMPLE VI 3-[3-(t-BUTYLAMlNO)-2- HYDROXYPROPOXY]-5-HYDROXYBENZYL ALCOHOL FUMARATE An ethanol solution (250 ml) containing 19.7 g (54.7 mmol) of 3-benzyloxy-5-(3-t-butylamino-Z-hydroxypropoxy)-benzyl alcohol was hydrogenated over 8 g of EXAMPLE VII 3-BENZYLOXY-5-[3-(t-BUTYLAM1NO)-2- HYDROXPRQPOXYl-BENZYL ALCOHOL To a suspension of 29.1 g (68.5 mmol) of methyl 3- benzyloxy-S-(3-t-butylamino-2-hydroxypr0poxy)benzoate in 500 ml of THF cooled at was added 5.20 g (137 mmol) of LiAlH The resultant mixture was refluxed 18 hours. After the excess LiAlH, and complex had been destroyed by the addition of water. the reaction mixturewas diluted with 500 ml ofCHCL and the precipitate was removed by filtration. The organic filtrate was washed with water (1x500 ml), dried with MgSO, and evaporated to give the crude solid product; yield 20.7 g mp 99105. The analytical sample was obtained from cyclohexane, mp 105107.

Anal. Calcd for C H NO C, 70.17; H, 8.13; N, 3.90. Found: C, 70.18; H, 8.01; N, 4.00.

EXAMPLE VIII I METHYL 3-BEN ZYLOXY-5-[3-(t- BUTYLAMINO)-2-HYDROXYPROPOXY]- v BENZOATE HYDROCHLORIDE W 7 M N, 3.30; CI, 8.36. Found: C,-62.45; H. 7.25; N, 3.50; CI,

EXAMPLE 1x 3-[3,4-DIMETHOXYPHENYLETl-IYLAMINO)-2 HYDROXYPROPOXY]-5-HYDROXYBENZYL LC FUMARA E To a suspension of 3.11 g (82.0 mmol) of LiAlH in 250 ml of dry tetrahydrofuran, was added a THF solution (250 ml) containing 20.3 g (41.0 mmols) of methyl 3-benzyloxy-5-[3-(3,4-dimethoxyphenylethylamino)-2-hydroxypropoxyl-benzoate. The resulting reaction mixture was refluxed for 3 hours before excess LiAlH, and complex was destroyed by the careful addition of water. Thewhite precipitate which formed was removed by filtration and the filtrate obtained was evaporated in vacuo and gave a quantitative yield of the crude 3-benzyloxy-5-[3-(3,4-

dimethoxyphenylethylamino)2-hydropropoxyI-benzyl alcohol as a straw colored oil.

An ethanol solution ml) containing 19.6 g (41.2 mmols) of 3-benzyloxy-5- [(3,4- dimethoxyphenylethylamino)-2-hydroxypropoxylbenzyl alcohol was hydrogenated over 5.0 g of 10% Pd/C catalyst until hydrogen uptake had ceased. The catalyst was removed by filtration and the filtrate was evaporated to give an oily residue as product. A crystalline hemifumarate salt was obtained from l-propanol; yield 14.1 g, mp 183186 dec. The analytical sample was obtained by one recrystallization from methanolet h er; mp 189191 dec.

Anal. Calcd for 0 11 610,. /2 c,H,o, c. 60.68; H. 6.71; N. 3.22. Found: c 60.60; H. 6.87; N, 3. 5.

EXAMPLE x METHYL 3-[3-(t-BUTYLAMlNO)-2- HYDROXYPROPOXY ]-5'- HYDROXYBENZOATE FUMARATE dec. The analytical sample was obtained from MeOH- Anal. Calcd for C H NO C I-I O,: C, 57.45; H, 7.09; N, 3.94. Found: C. 57.26; H, 7.15; N, 3.75. 3-[3- (3,4-dimethoxyphenylethylamino)-2- hydroxypropoxyl-5-hydroxybenzyl alcohol, prepared as in Example IX, was tested for determining ,B-adrenergic receptor agonist/antagonist-evaluation in the ganglion blocked or reserpinized dog. The dosage necessary to block the isoproterenol (0.3 ,ug/kg. i.v.) response was tested for both myocardial (Beta,) and peripheral (Beta blood force; dosages showing intrinsic sympathomimetric activiity and direct myocardial depression were also determined. The ganglion blockage was accomplished by treating the dogs prior to testing with 2 mg/kg of ansolysen or reserpine. The results are foundin Table 1 This testing showed the Example IX compound to be a potent and competitive B-adrenergic receptor antagonist. It has intrinsic sympathomimetic activity at doses causing minimal Beta blockage. Example A compound is a cardioselective ,B-adrenergic blocker i.e., there appears to be about a 3-fold difference in the dose blocking Beta, and Beta receptors. Furthermore it is less cardiodepressant than propanolol with only minimal depressant activity at doses up to 30 mg/kg. After a cardiodepressant dose of propranolol 10 mg/kg on top of a total of 14.4 ing/kg of test compound. an additional 10 mg/kg of test compound caused no further direct myocardial depression.

TABLE I Beta Blocker Evaluation in the Vagotomized Dog Of Compound Example IX Dose. mg/kg. i.v.. necessary to block the lsoprotercnol (0.3 tg/kg. i.v.) Response Beta (Peripheral Intrinsic Dose. mg/kg Vasculature) Sympathomimctic Causing Direct Beta. (Myocardial) Diastolic Blood Activity Myocardial Expt. Pretreatment Force and Rate Pressure mg/kg Depression 1 Ansolysen 3 1.0 1.0 0.03 3t) (slight) 2 Ansolysen 0.3 1.0 1.0 0.03 10 (slight) 3 Ansolysen 0.3 1.0 3.0 00} 10 (slight) 4 Reserpine 1.0 3.() ().03 10 The compound was also tested for ouabain-induced arrhythmia in which 2 mg/kg of the test compound are given [.V. After any effects have been observed for -30 minutes, ouabain is given I.V. until the appearance of ventricular tachycardia. After arrhythmia has developed, 5 mg/kg of test compound are administered and the effects observed. Results showed that the compound was devoid of antiarrhythmic activity.

3-13-(tert-butylamino)-2-hydroxypropo xy]-5- hydroxybenzyl alcohol, prepared as in Example V1, was tested for an evaluation of its direct myocardial depressant activity as compared with the known Beta receptor antagonist propranolol.

Standard laboratory procedures were followed. In addition a segment of the circumflex coronary artery of the dog was isolated and partially occuluded so as to depress myocardial contractility by approximately 50% (contractile force was measured using the Walton Brodie Strain Gauge). Following stabilization of the preparation equiactive i.v. doses of the antagonists were administered: the test compound (0.5 mg/kg) and propranolol (1.0 mg/kg). Doses of each compound were repeated and administered in a random fashion.

The test compound did not depress myocardial contractility in addition to the depression caused by coronary occulsion alone. Propranolol had a negative inotropic action after 1.0 mg/kg. The test compound was negatively inotropic at 2.0 mg/kg.

The test compound caused less of a negative inotropic response than propranolol at equiactive Beta blocking doses, and did not appear to have any intrinsic sympathomimetic properties in the ganglion blocked dog.

A summary of the pharmcology of the two compounds tested above can be seen in the following Table 11:

TABLE 11 (slight) tered in anesthetized, reserpinized, vagotomized adult mongrel dogs.

A second analog of this invention where R,=CH OH. R =H, and R =3,4-dimethoxypheny1ethyl (Example IX) demonstrates potent B-adrenergic blocking activity which is selective for the B-receptors of the myocardium compared with peripheral vascular B-receptors. Generally, a dose of 0.1-3.0 mg/kg, iv. is required to totally block the myocardial response to isoproterenol(0.3 pg/kg, iv.) administered in anesthetized, reserpinized, vagotomized adult mongrel dogs. This analog has possible advantage over other cardioselective B-adrenergic blockers such as practolol since it is a more potent cardioselective agent with low toxicity.

The cardioselective ,B-adrenergic blocking agents of this invention are therapeutically preferred over nonselective B-blockers in cases where patients are suffering from bronchial constriction due to asthma or similar conditions. Non-selective ,B-blockers would be expected to aggravate bronchial constriction under those conditions.

Accordingly we claim:

1. A compound of the formula:

a J i Dose* (mg/Kg. iv.) to Totally Block Myocardial Compound Response to lsoproterenol Dose (mg/Kg. iv.) Causing Direct Myocardial Depression Propranolol 0.5 mg Example V1 Example 1X Qua g mg mg 2 mg (slight) 10 30 mg (slight) Dose. mg/Kg. iv.. necessary to totally hlock heart response to isoprotcrcnol (L3 pig/Kg i\-.

in dog [\ugolomizcd und ganglionic blocked by unsolyscn).

Specifically, the analog where R =CH OH. R =H.

and R =t-butyl (Example V1) elicits potent B-adrcnerwherein R is selected from the group consisting of:

and on, and

9 wherein R is selected from the group consisting of: and R is H ,7 Ills l:--- on. .3 CH 5 (iii i 7. The com pound according to claim I wherein R, is CH -COOCH;| R is 3 v I ocn C CH and 3 l I and R is -(lil (.ll ooii Z 2 3 CH CH 0 I )(Jll .s 9 a ll and the pharamceutically acceptable salts of the above The Compound according to claim I wherein is compound. iCHz R 15 2. The compound according to claim 1 wherein R is aw CH OH; R is OH; and R is i -o(;|-i

3 i c- 3 and R is H3 is a .7 -CH2CH2 OLH 3. The compound according to claim 1 wherein R is CH OH R isO H a nd i1; is V H H I 3 I OCH z l Q B 9. The compound according to claim 1 wherein R is do n 7 -co0cH R is 4. The compound according to claim 1 wherein R is Y COOCH R is OH; and R is 2 W3 40 i i C- CH and R318 V v I *CH 5. The compound according to claim 1 wherein R is 2 CH OH; R is OCH v 10. The compound according to claim I wherein R 2 is CH OH; R is and R is C 0CH2 1H i C CH,

I and R is CH3 I 6. The compound according to claim 1 wherein R is COOCH R is g g H V 11. The compound according to claim 1 wherein R -ocn is CH OH; R is OH; and R is H.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3793365 *Apr 10, 1970Feb 19, 1974Boehringer Mannheim GmbhAmino acid derivatives
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3949088 *Apr 16, 1974Apr 6, 1976Benny Roger SamuelssonSubstituted phenoxy propanol amines used for treating cardiovascular diseases
US4161530 *Mar 17, 1978Jul 17, 1979Ciba-Geigy CorporationPharmaceutical combination preparations as hypnotics
US4191765 *Aug 10, 1978Mar 4, 1980Hoechst Aktiengesellschaft1-Aryloxy-2-hydroxy-3-aminopropanes
US4309443 *Sep 3, 1980Jan 5, 1982Beecham Group LimitedAnti-obesity, hypoglycemic
US4999378 *Jun 20, 1989Mar 12, 1991Otsuka Pharmaceutical Company, LimitedPhenylcarboxylic acid derivatives
WO1982001869A1 *Nov 16, 1981Jun 10, 1982American Hospital Supply CorpMethod for treatment or prophylaxis of cardiac disorders
Classifications
U.S. Classification560/42, 546/236, 560/45, 546/240, 544/172, 514/821, 560/65, 564/349, 544/174, 546/239, 560/66, 546/238, 562/451, 560/67, 250/396.00R
International ClassificationC07D303/24
Cooperative ClassificationY10S514/821, C07D303/24
European ClassificationC07D303/24